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A complication of end-stage liver disease which occurs in patients who have chronic liver dysfunction with cirrhosis and ascites and also in acute liver failure. In hepatorenal syndrome (HRS) there is impaired renal function which is often precipitated by events lowering blood pressure - for example, bacterial infections, large volume paracentesis without volume expansion, or haemorrhage (hypovolaemia).
Hepatorenal syndrome (HRS) is a common complication of end-stage liver disease but there are no recent data on the prevalence or incidence.
Diagnostic criteria for hepatorenal syndrome
Hepatorenal syndrome (HRS) is essentially a diagnosis of exclusion - ie there is an absence of other identifiable causes of renal failure.
The diagnostic criteria have recently been defined and are as follows:
- Cirrhosis with ascites
- Serum creatinine >1.5mg/dl (133μmol/L)
- Absence of shock
- Absence of hypovolemia as defined by no sustained improvement of renal function (creatinine decreasing to <133μmol/L) following at least 2 days of diuretic withdrawal (if on diuretics), and volume expansion with albumin at 1g/kg/day up to a maximum of 100g/day
- No current or recent treatment with nephrotoxic drugs
- Absence of parenchymal renal disease as defined by proteinuria <0.5g/day, no microhaematuria (<50 red cells/high powered field), and normal renal ultrasonography
HRS is probably the result of a combination of the following: splanchnic vasodilatation leading to systemic circulatory dysfunction, activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, and changes in cardiac output (usually low, but is always less than the patient's requirements). In addition there is enhanced release of vasoactive mediators, eg thromboxane A2 and endothelin-1. The end result is intrarenal arteriolar vasoconstriction.
Hepatorenal syndrome (HRS) has been divided into two types depending on rate of progression:
- Type 1 - defined as a doubling of serum creatinine to >221 μmol/L in less than 2 weeks, ie rapidly progressing. These patients have a very low glomerular filtration rate (GFR) (<20 ml/minute) and very poor prognosis. This is usually associated with a precipitating event, eg variceal bleed, spontaneous bacterial peritonitis.
- Type 2 - defined as a more gradual decline in renal function, associated with sodium retention and refractory ascites.
Patients with type 2 HRS can go on to develop type 1 HRS following a precipitating event.
Patients with ascites and other signs of severe liver disease (jaundice, bleeding disorders, malnutrition, stigmata of chronic liver disease) develop renal failure (oligouria or just increasing serum creatinine levels). There is salt and water retention with increased ascites and peripheral oedema - although pulmonary oedema is uncommon. Hyponatraemia is almost universally present (dilutional hyponatraemia); hyperkalaemia is common (and should be aggressively treated).
- Spontaneous bacterial peritonitis - 30% will develop hepatorenal syndrome (HRS).
- Gastrointestinal (GI) tract bleed.
- Superimposed infections, eg pneumonia.
This is made after excluding other causes of renal failure in patients with liver failure:
- Pre-renal causes (eg whether there is history of dehydration, over-diuresis, GI fluid loss).
- Any nephrotoxic drugs?
- Whether there is history of shock before renal failure (which would suggest acute tubular necrosis).
- Whether there is any proteinuria ± haematuria, suggesting a parenchymal renal disease (renal ultrasound scan may be helpful) - particularly, glomerulonephritis (associated with hepatitis B/hepatitis C or chronic alcoholism).
Type 1 hepatorenal syndrome (HRS)
- Admit to hospital - ideally to the high-dependency unit.
- Monitor fluid status closely - eg urine output and CVP monitoring which will help guide fluid replacement.
- Restrict fluids if necessary.
- Treat any precipitating infections aggressively. If there is no clear focus of infection patients should still be started on broad-spectrum antibiotics - and a full course completed.
- Avoid nephrotoxic drugs and stop diuretics.
- Start splanchnic vasoconstrictors, eg terlipressin in combination with albumin replacement.
- Terlipressin leads to an increased blood pressure and GFR, through constriction of splanchnic blood vessels.
- Monitor closely for: ischaemic heart disease, arrhythmias, fluid overload and digital ischaemia.
- Alternatives include norepinephrine or midodrine (unlicensed in the UK) and octreotide, although at present there is little experience of using these drugs.
Transjugular intrahepatic portosystemic shunt (TIPS):
- TIPS is used to reduce ascites in patients with portal hypertension, in those who do not respond to vasoconstrictors.
- It is contra-indicated in severe liver failure, which has limited its use.
- Studies have not reported TIPS to be associated with increased survival in type 2 HRS.
- The best chance of long-term survival would seem to be liver transplantation.
- Renal replacement therapy (RRT) may be necessary, eg pulmonary oedema, severe hyperkalaemia or metabolic acidosis not responding to other treatment. Yet there are no data suggesting improvements in survival in HRS with RRT.
Type 2 HRS
- Patients who develop type 2 HRS may need to be admitted and treated as type 1 HRS.
- Some patients with type 2 HRS can be treated on an outpatient basis with sodium restriction and diuretics (eg spironolactone - monitor for hyperkalaemia).
- Elective admissions with repeated paracentesis may be necessary to control gross ascites.
- TIPS can be used in refractory cases and may be more feasible than in type 1 HRS.
- Liver transplantation is the best option for both types 1 and 2 HRS (whether or not they respond to vasoconstrictors).
- Combined kidney and liver transplant may be needed in patients with HRS who require prolonged renal support (ie >3 months).
Life-threatening bacterial infections (septicaemia, spontaneous bacterial peritonitis, pneumonia).
Hepatorenal syndrome (HRS) is associated with low survival, with an average median survival rate of only 3 months for type 1 HRS and 6 months for type 2 HRS. Liver transplantation in both type 1 and type 2 HRS improves survival, with rates of 65% in type 1 HRS reported.
Further reading & references
- Gines P, Guevara M, Arroyo V, et al; Hepatorenal syndrome. Lancet. 2003 Nov 29;362(9398):1819-27.
- Management of Ascites Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome in Cirrhosis; European Association for the Study of the Liver (2010)
- Salerno F, Gerbes A, Gines P, et al; Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007 Sep;56(9):1310-8. Epub 2007 Mar 27.
- Gines P, Uriz J, Calahorra B, et al; Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis. Gastroenterology. 2002 Dec;123(6):1839-47.
- Sort P, Navasa M, Arroyo V, et al; Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999 Aug 5;341(6):403-9.
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Dr Huw Thomas
Dr Gurvinder Rull